Lemtrada (alemtuzumab)

The U.S. Food and Drug Administration has approved Sanofi's multiple sclerosis treatment Lemtrada, Sanofi said in a statement on Saturday.

Lemtrada is already sold in Europe but last December U.S. regulators rejected it on security concerns, prompting analysts to slash their global sales forecasts for the drug.

Sanofi said in its statement that "because of its safety profile" the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Lemtrada is given in two courses via an intravenous drip for five days and for three days one year later.

It is designed to re-program the immune system, but in doing so can make the body more vulnerable to other diseases. FDA staff had last year flagged risks of autoimmune diseases including blood disorders, infections and cancer.

Lemtrada was at the core of Sanofi's $20 billion 2011 takeover of U.S. biotech Genzyme, which developed the drug.

Sanofi's chief executive at the time, Chris Viehbacher, who was sacked by Sanofi's board last month, had championed the move into rare diseases as he sought new areas of growth to offset the impact of patent losses on big-selling drugs.

Multiple sclerosis is a chronic, autoimmune condition which affects more than 2 million people worldwide and up to 500,000 in the United States. It attacks the central nervous system and can cause muscle weakness, pain and cognitive difficulties.

The multiple sclerosis market is increasingly moving away from injectable treatments in favour of pills such as Novartis' Gilenya and Biogen Idec's Tecfidera.

But Genzyme hopes Lemtrada's ability to reduce the risk of relapse of the disease will win it market share.

Industry observers however expect it will be reserved for patients for whom other treatments are ineffective. Analysts on average expect the drug to generate sales of just $141 million next year and just under $400 million by 2018, according to Thomson Reuters Cortellis data.

Germany's Bayer has an option to co-promote Lemtrada in the United States.

Genzyme's plans to grow its multiple sclerosis business in Europe continued with the launch of two new treatments in the Republic of Ireland.

The company, which serves as the biotech arm of French pharma firm Sanofi, today launched the injectable Lemtrada (alemtuzumab) in the country just weeks after oral multiple sclerosis (MS) treatment Aubagio (teriflunomide) hit the market.

Lemtrada will be made available to adults with active relapsing-remitting multiple sclerosis (RRMS), in accordance with its approval from the EC. It is to be given as an intravenous infusion in two annual treatment courses.

Aubagio is also available for adults with active RRMS, although it is one of several new MS treatments that come in an oral formulation, offering greater convenience to patients. It is to be taken once daily.

According to Genzyme, there are 8,000 people in Ireland with MS and around 85% will be affected by RRMS.

The launch of Lemtrada follows a recommendation in July this year from the National Centre for Pharmacoeconomics (NCPE), which provides guidance on what drugs should be reimbursed on Ireland's healthcare system to the Health Service Executive (HSE).

By contrast, Aubagio was turned down by the NCPE in June with after its assessment found that the drugs cost was not justified by its benefits.

However, in a conversation with PMLiVE, Henry Featherstone, director of public affairs at Genzyme UK & Ireland confirmed that Genzyme has since held discussions with the HSE and they have agreed that the drug can be reimbursed in Ireland.

As for where the drugs fit on the MS treatment pathway, Featherstone said that the broad indications for both products allowed doctors to discuss suitable options with patients. Further down the line, however, it's possible that Aubagio will be better suited as a first-line treatment for people with MS, while Lemtrada will be reserved for more aggressive forms of the disease.

"We hope to have these treatments available to as many people with MS as possible," Featherstone told PMLiVE. "We passionately believe in these products."

Backing Featherstone's belief, both drugs are making headway in western Europe where Lemtrada had revenues of €10m for the first six months of the year and Aubagio had revenues of €38m.

It's a different story for Lemtrada in the US, however, as the drug was turned down by the FDA at the start of 2014, much to the shock of Genzyme and Sanofi.

The decision, which was based on concerns over the drug's safety, drew criticism from the healthcare community and dozens of US doctors added their name to an open letter to the FDA to appeal the negative guidance.

"Scotland has one of the highest rates of multiple sclerosis in the world, and the approval of Lemtrada in Scotland is an important step forward for people with active RRMS who remain in need of new treatment options. MS treatments have come a long way in the past twenty years and the availability of Lemtrada provides an opportunity for neurologists to offer a new therapy to people with multiple sclerosis," commented Dr. Belinda Weller, Consultant Neurologist, Western General Hospital, Edinburgh.

The Scottish Medicines Consortium (SMC) today published its advice that Lemtrada has been accepted for use within NHS Scotland for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS), with active disease defined by clinical or imaging features.

"RRMS accounts for eighty-five percent of all initial diagnoses in MS. We are pleased that after many years in development, Lemtrada is now available to patients in Scotland. This provides people with MS with an important and innovative treatment option to consider in partnership with their MS specialists," said Amy Bowen, Director of Service Development at the MS Trust.

There are approximately 10,000 people living with MS in Scotland. The majority of people with RRMS experience approximately one or two relapses per year. Around half of all relapses may leave people with lingering problems and disability may accumulate over time.[

Lemtrada is the second of Genzyme's treatments for MS to receive approval for use from the SMC and become available for use within NHS Scotland.Lemtrada has also been approved by NICE and is available for NHS patients in England & Wales.

"We are thrilled by today's news that the SMC has approved Lemtrada for NHS use for people with RRMS. At Genzyme, patients at the heart of everything we do and this final milestone brings a treatment option to people with MS that could really reshape the management of their condition. We are also immensely proud of our association with Lemtrada as a home-grown product, developed and pioneered in Cambridge by a team of UK scientists. This reminds us of the UK's position at the forefront of science-led medicine, the importance of industry collaboration which brings global expertise in clinical development and our joint commitment to MS patients," commented Brendan Martin, General Manager for Genzyme UK and Ireland.

The US Food and Drug Administration (FDA) has accepted for review the Genzyme's resubmission of supplemental Biologics License Application (sBLA) seeking approval of Lemtrada (alemtuzumab) for the treatment of relapsing forms of multiple sclerosis. A six-month review period has been assigned for the Lemtrada sBLA. Genzyme expects FDA action on the sBLA in the fourth quarter.

This resubmission is based on data from the same clinical studies included in the original sBLA, and provides supplemental analyses and additional information to specifically address issues previously noted by the FDA in its December 27, 2013 Complete Response Letter. The company resubmitted the sBLA earlier this month following constructive discussions with the agency.

Serious questions remain regarding the side effects and benefits associated with the use of alemtuzumab for the treatment of multiple sclerosis.

The 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) concluded Saturday with “Controversies in the Treatment of Multiple Sclerosis,” a debate-style session that focused on discussion of several hot-button issues in current practice. The third and final segment, “Controversy III: Alemtuzumab is Too Toxic to Use in Most Patients with MS,” featured a debate over the benefit vs. risk profile of alemtuzumab, an anti-CD52 monoclonal antibody that is currently approved for the treatment of several forms of leukemia and lymphoma and is being studied for the treatment of multiple sclerosis.

Late last year, the FDA rejected the drug for the treatment of multiple sclerosis, saying that more evidence from high-quality clinical trials was need regarding the benefits and risks of the drug in this patient population.

One participant in the debate session, Olaf Stüve, MD, PhD, said “there is a need for more effective yet safe therapies; currently available treatment options are only partially effective and have potentially life-threatening side effects.”

Stüve is associate professor in the Department of Neurology and Neurotherapeutics and associate professor in the Department of Immunology at University of Texas Southwestern Medical Center, and chief of the Neurology Section at VA North Texas Health Care Systems.

The clinical phase II CAMMS223 study (which was not an open-label study) compared alemtuzumab with interferon beta-1a in patients with early, active relapsing-remitting multiple sclerosis. Over five years of follow up, researchers found that treatment with alemtuzumab lowered the risk of sustained accumulation of disability by 72% compared with interferon beta-1a. Treatment with alemtuzumab also lowered relapse rate by 69% compared with interferon beta-1a. In the CARE-MS I trial, treatment with alemtuzumab led to a 55% risk reduction in relapses compared with interferon beta-1a.

Stüve also noted that in CARE-MS II the secondary co-primary endpoint (sustained accumulation of disability) was met and there was a 42% improvement in risk reduction in the alemtuzumab group compared with the interferon beta-1a group.

“Alemtuzumab is highly effective; with it patients can be treated early to prevent accumulation of disability,” he said.

“There is no need to treat patients long-term, sides effects are mostly mild to moderate, disease and organ specific, and a pharmacovigilance program could be established to screen patients,” said Stüve.

Fellow debater, Mitchell Wallin, MD, MPH, disagreed, pointing out that there are “serious GI side effects” associated with treatment with alemtuzumab, including abdominal pain and flushing.

Wallin is Clinical Associate Director of the Multiple Sclerosis Center of Excellence based in the Baltimore Veterans Affairs (VA) Medical Center/University of Maryland, and associate director of Clinical Care and associate professor of medicine at Georgetown University.

He noted there are also concerns over treatment adherence and challenges of maintaining long term injection. Adherence to self-administered disease-modifying therapies in multiple sclerosis has been the subject of several papers. Based on study results, between 12-87% of patients with multiple sclerosis do not adhere to their disease-modifying therapies.

In addition, because of the risk for life-threatening infections, rapid diagnosis of autoimmune cytopenias is imperative. He said the company had recommended monitoring complete blood count in patients.

If approved for the treatment of multiple sclerosis, the drug would have to have labeling regarding the risks, said Wallin.

- Scientists have spent 25 years developing treatment at Cambridge - Alemtuzumab infusion is given in two short courses over two years - Despite costing £56,000, NICE has ruled treatment is cost-effective

A new treatment for Multiple Sclerosis not only stops the disease from advancing but may help patients recover from disability.

Remarkable results for the drug alemtuzumab mean it has been approved for use on the NHS and is now available in England.

Originally a pioneering cancer therapy, Cambridge University scientists have spent almost 25 years developing it as a treatment for MS patients.

Trials involving more than 1,500 patients show treatment led to fewer relapses compared with multiple jabs of the treatment beta interferon each week, cutting further disability and even allowing some existing damage to recover.

Alemtuzumab is given in two short courses with one infusion a day for five days during the first year and three days during the second year followed by regular monitoring. Despite the £56,000 price tag, the drug has got the go-ahead as cost-effective from the rationing watchdog the National Institute for Health and Care Excellence (Nice). Professor Alastair Compston, Professor of Neurology and the Head of the Department of Clinical Neurosciences at the University of Cambridge, said the drug worked in the early stages of MS, but did not help patients with advanced disease.

Multiple Sclerosis affects almost 100,000 Britons, causing attacks or relapses that may lead to progressive loss of physical skills, sensation, vision, bladder control, and intellectual abilities.

Prof Compston said more than half of patients with this type of MS could benefit.

He said ‘This is a real step forward and brings to a conclusion work involving a number of research groups in Cambridge, stretching back to 1991.

‘The decision from Nice now provides an opportunity for neurologists to offer a highly effective therapy for patients with multiple sclerosis early in the course of their illness.’

Alemtuzumab, marketed as Lemtrada by makers Genzyme, was being used in chronic lymphocytic leukaemia when Prof Compston identified its potential for treating MS.

It works by destroying a key class of immune cells that are attacking the body’ s healthy nerve cells and then rebooting the immune system so it no longer turns on itself. A main side effect is patients can develop other autoimmune diseases as the immune system gradually recovers following exposure to the drug.

These include thyroid problems and a low blood platelet count that can rarely can prove fatal. Platelets are cells that circulate in the blood and clot to keep us from bleeding. The complications can be easily treated if promptly recognised which makes monthly blood tests essential, said Prof Compston.

‘This drug offers a bright future but it is coloured by the risk.

‘It’s not a cure and it doesn’t work for everyone but it can stabilise the disease for a long time. Patients are less disabled, they can look after their families and the societal savings are considerable’ he added.

Unlike most treatments newly approved for NHS use, patients don’t have to try other drugs first and more than two courses of treatment may be offered.

Prof Compston said ‘Twenty years ago when a young person was diagnosed, I’d have to say I’m sorry to tell you that you do have MS – we’ll do our best to look after you but there are limited treatments.

‘Today this drug may well be suitable for 50 to 60 per cent of early cases.’

Nick Rijke, Director for Policy & Research at the MS Society, said it was ‘a major step forward’.

He said ‘This drug has taken decades to develop, and we applaud the team at Cambridge for all their work in making it a reality.

‘While it’s not without risk, it’s proven to be a highly effective medicine for people with relapsing remitting MS and we look forward to seeing it made available to those who could benefit.’

Amy Bowen, of the MS Trust said ‘This provides people with MS with an important treatment option to consider in partnership with their MS specialists.’

Objective: To test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 106 cells/mL at 12 months can be used to identify patients who may benefit from further treatment.

Methods: A total of 108 patients were followed for a median of 99 months post alemtuzumab. Patients were classified as active or nonactive after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts.

Results: Of 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment.

Conclusion: This study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab.

- Approximately 80 percent of patients treated with Lemtrada did not receive a third course of treatment in the first year of the extension.

Genzyme , a Sanofi company , announced today new magnetic resonance imaging (MRI) data from the Lemtrada (alemtuzumab) clinical development program. In Lemtrada patients from the two Phase III clinical trials (both treatment-naïve patients and patients who had active disease on another therapy), MRI effects observed after two years were maintained during the first year of the extension study. These data, which are being presented today at the 66th American Academy of Neurology (AAN) Annual Meeting, include:

Consistent effects were seen across key measures of disease activity (gadolinium (gd)-enhancing, T2 hyperintense and T1 hypointense lesion activity) and effects seen after two years of treatment were sustained at year three.

During the third year of follow-up, more than 70% of patients were free of MRI activity indicative of acute inflammation, defined as gd-enhancing or new or enlarging T2 hyperintense lesions.

T2 lesion volumes, which reflect the combined burden of permanent brain injury and new lesion formation, increased from year two to three but remained below pre-treatment baseline.

The rate of atrophy, as measured by brain parenchymal fraction, already reduced after two years, continued to slow in the third year of follow-up.

Approximately 80 percent of patients treated with Lemtrada did not receive a third course of treatment in the first year of the extension.

“What’s remarkable about these data is that the positive MRI effects of Lemtrada were sustained into the extension study, even though most patients did not receive additional Lemtrada treatment. This observation is unique amongst the current landscape of MS therapeutics,” said Douglas Arnold, M.D., NeuroRx Research and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University. “The new MRI results are an important addition to the clinical data from the extension study that demonstrated Lemtrada’s effect on key measures of clinical disease activity including annualized relapse rates and sustained accumulation of disability.”

The most common side effects of Lemtrada are infusion associated reactions (headache, rash, pyrexia, nausea, fatigue, urticaria, insomnia, pruritus, diarrhea, chills, dizziness, and flushing), infections (upper respiratory tract and urinary tract), and lymphopenia. Autoimmune conditions (including immune thrombocytopenia, other cytopenias, glomerulonephritis and thyroid disease) and serious infections can occur in patients receiving Lemtrada. A comprehensive risk management program incorporating education and monitoring will support early detection and management of these identified risks. Safety results from the first year of the extension study were previously reported for patients who received Lemtrada in the Phase III CARE-MS studies. No new risks were identified. As previously reported, there were two deaths in the extension study. One was from sepsis and the other was presumed accidental and deemed unrelated to study treatment.

The Phase III trials of Lemtrada were randomized, two-year studies comparing treatment with Lemtrada to high-dose subcutaneous interferon beta-1a (Rebif®) in patients with RRMS who had active disease and were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). In these studies, patients on Lemtrada received two courses of treatment, the first administered via intravenous infusion on five consecutive days, and the second administered on three consecutive days, 12 months later.

Lemtrada-treated patients who continued uninterrupted follow-up in the extension study were eligible for re-treatment on evidence of disease activity. This analysis included 349 Lemtrada-treated patients from CARE-MS I and 393 Lemtrada-treated patients from CARE-MS II; 18 percent and 20 percent, respectively, received re-treatment. MRI scans were taken at CARE-MS baseline, and at 12, 24, and 36 months.

“Given the importance of MRI in measuring disease activity in MS, the Lemtrada data announced today are significant,” said Genzyme President and CEO, David Meeker, M.D. “These results reinforce the potential that Lemtrada holds to transform the treatment of MS.”

In CARE-MS I, Lemtrada was significantly more effective than interferon beta-1a at reducing annualised relapse rates; the difference observed in slowing disability progression did not reach statistical significance. In CARE-MS II, Lemtrada was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in patients given Lemtrada vs. interferon beta-1a.

Nearly four months after the Food and Drug Administration rejected a multiple sclerosis drug developed by Genzyme, citing the clinical trial’s design and a risk of serious side effects, the Cambridge biotech said Monday that it will resubmit an application for approval to the agency.

Rather than appeal the FDA’s decision, as expected, Genzyme said it will file an updated license application for the drug candidate, called Lemtrada, in the second quarter. The new submission will specifically address issues raised by the FDA in its Dec. 27 decision turning down the experimental treatment, Genzyme said in a statement.

The move follows a series of discussions early this year between Genzyme executives and regulators in the neurology products division of the FDA’s Office of Drug Evaluation, said Genzyme spokeswoman Erin Walsh. She declined to elaborate on the talks and said company officials would not comment until after they resubmit their application. But she did say the drug maker has no plans to conduct additional clinical studies before the FDA rules.

“We had constructive discussions with the FDA that have led us down this path where we’re resubmitting our application rather than filing an appeal,” Walsh said. “We don’t believe further trials are needed prior to an approval. But we would entertain any kind of post-approval commitments” to the FDA, including possible further tests of the drug, she said.

Similarly, FDA officials would not talk about Genzyme’s plans to resubmit its Lemtrada application.

The agency rejected the drug for use in the United States, even though it had been approved by regulators in Europe, Canada, and Australia. The decision was criticised by MS patients, who said the drug had proven effective in clinical trials, and by investors who own a special class of stock that is tied to Lemtrada’s regulatory and sales milestones.

“We are not able to discuss any aspect of a drug application that is under agency review,” said FDA spokeswoman Sandy Walsh. In November, an FDA advisory committee warned that the drug’s side effects could include rashes, bleeding, and even thyroid cancer.

Genzyme scientists spent more than a decade developing Lemtrada for the treatment of multiple sclerosis, a disease that affects the central nervous system. About 1,700 patients were involved in clinical testing of the drug. More than 2.3 million people have been diagnosed with MS worldwide, including about 400,000 in the United States.

The potential of that market, and anticipation that Lemtrada would be approved in the United States, was a major attraction for the French drug maker Sanofi SA, which paid $20.1 billion to acquire Genzyme in 2011. In that deal, Sanofi agreed to reward former Genzyme stockholders if the drug achieved certain milestones in the US market.

In final draft guidance, UK drugs watchdog the National Institute for Health and Care Excellence (NICE) has recommended the use of French drug major Sanofi (Euronext: SAN) subsidiary Genzyme’s multiple sclerosis drug Lemtrada (alemtuzumab).

The NICE is appraising alemtuzumab as a treatment for adults with relapsing–remitting multiple sclerosis, a chronic and disabling neurological condition that, as it progresses, can have a substantial negative impact on a person’s quality of life.

Currently available treatments for this type of MS are either oral daily tablets or injections given several times each week and can have unpleasant side effects. The NICE pointed out. Alemtuzumab is taken intravenously once a year for two years. The first course is administered for five consecutive days, and the second course is administered for three consecutive days, 12 months later allowing those with the condition to lead their lives without treatment for the rest of the time. Alemtuzumab does have some possible side effects associated with it which, according to clinical specialists, are manageable. Compared with most available treatments, alemtuzumab has a shorter time period during which it is not recommended that a person gets pregnant. This could be seen as advantageous for patients who are planning to have a baby.

Carole Longson, NICE Health Technology Evaluation Centre director, said: “We are very pleased to be able to recommend alemtuzumab for adults with relapsing-remitting multiple sclerosis. Following a request for more information by our independent Appraisal Committee, the manufacturer was able to provide further evidence, which has led to this positive recommendation.”

Until the NICE issues final guidance, National Health Service bodies should make decisions locally on the funding of specific treatments. Once NICE issues its guidance on a technology it replaces local recommendations across the country.

Pricing to be confirmed

The indicative price of alemtuzumab is £7,045 ($9,722) per 12 mg vial, which equates to £56,360 for the full course of treatment consisting of five daily consecutive 12mg doses in year one, followed by three daily consecutive 12mg doses 12 months later in year twp. The price of alemtuzumab has not yet been confirmed by the Department of Health. However, the Department has exceptionally agreed for this indicative price to be used for the purpose of this appraisal. Costs may vary in different settings because of negotiated procurement discounts.

Last year, when issuing draft guidance (The Pharma Letter December 5, 2013), Prof Longson said: “When reviewing the evidence for alemtuzumab, the Appraisal Committee concluded that there were still questions to be answered. This is why we have requested more details from the manufacturer; to ensure that we have the information the Appraisal Committee needs to reach their conclusions.”

ANVISA, Brazil’s national health surveillance agency, has approved Sanofi company Genzyme's Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS) to slow or reverse the accumulation of physical disability and reduce the frequency of clinical exacerbations.

Lemtrada is supported by a clinical development program that involved about 1,500 patients and 5,400 patient-years of follow-up.

The approval in Brazil follows the recent approvals of Lemtrada in Mexico, Canada, Australia and the European Union (EU).

The company said that lemtrada is currently not approved in the US.

In December 2013, the company secured a complete response letter from the US FDA on its application for US approval of Lemtrada and announced its intent to appeal this decision. Marketing applications for Lemtrada are also under review in other countries.

Brazil's Hospital da Restauração head of Neurology Maria Lucia Brito Ferreira said lemtrada is an new treatment, with clinical trial data that support its potential to meaningfully address relapse rates and disability in patients with active MS.

"Lemtrada will provide physicians with a promising new option for their patients with active MS and could change the way this disease is managed," Ferreira said.

The company said that Lemtrada 12mg has a new dosing and administration schedule of two annual treatment courses.

The first treatment course of Lemtrada is administered through intravenous infusion on five consecutive days, and the second course is given on three consecutive days, 12 months later.

Most common side effects of Lemtrada are infusion associated reactions, infections, lymphopenia and leukopenia.